Process for preparing dl-ribose and intermediates therefor



United States Patent This is a continuation-in-part application of our appli- 3,304,298 Patented Feb. 14, 1967 ing from 1 to 3 carbon atoms to form 1,1-dialkoxy-pent-.

2-yn-4,5-diol derivatives having the formula OR: (IV) wherein R and R have the same meaning as above, subcation Serial No. 187,199, filed April 13, 1962, and now abandoned.

This invention relates to a new process for preparing DL-n'bose.

Heretofore, there are described in literature a number of processes for preparing D-ribose. However, in these processes, D-ribose is obtained by conversion of monosaccharides, for example, partial decomposition of hexose or by extraction from natural substances. These processes are commercially disadvantageous because of their limited supply and high cost. As a result of studies made in order to discover commercially useful processes for the preparation of DL-ribose, it has now been discovered that by the total synthetic process as described below in details DL-ribose may be prepared in very high yield. Furthermore, it has also been found that the reaction in the fourth step in the process according to the present invention, which involves conversion of 2-alkoxy- S-hydroxymethyl-2,5-dihydrofuran derivatives having the below described Formula V to 2-alkoxy-3,4-dihydro xy-5- hydroxymethyl-tetrahydrofuran derivatives having the bei low described Formula VI by introduction of hydroxy groups, proceeds stereospecifically without formation of DL-lyxose, and consequently gives only the desired DL- n'bose in very high yield.

It is therefore an object of the invent-ion to provide a I sisting of Z-tetrahydropyranyl and Z-tetrahydrofuryl groups and R is a member selected fro-m the group con- 1 sisting of hydrogen atom, a lower alkyl group containing from 1 to 3 carbon atoms q and 0 O-CHz- 0 0CHz' to ozone oxidation to form glycol aldehyde derivatives having the formula RO CH -CHO (II) wherein R has the same meaning as above, reacting the latter compounds with propargyl acetal derivativeshaving the formula I M-CEC-CH wherein M is a member selected from the group consisting of an alkali metal and MgX in which X is a member selected from the group consisting of chlorine, bromine and iodine atoms and R is a lower alkyl group containwherein R is a member selected from the group conjecting the latter compounds to partial hydrogenation in the presence of a rare metal catalyst to form 2-a1koxy-S- hydroxymethyl-2,5-dihydrofuran derivatives having the formula ROGH L R T \O/ O 2 (v) wherein R and R have the same meaning as above, reacting the latter compounds with an oxidizing agent to form 2 alkoxy 3,4-dihydroxy-5 -hydroxymethy1-tetrahydrofuran derivatives having the formula OH OH I Room-i O/LORZ wherein R and R have the same meaning as above and treating the latter compound with a diluted mineral acid to form DL-ribose. These reactions in the process'according to the present invention may be chemically represented by the following equation:

'DL-rlbose Insthe above formula, R, R meaning as above. I

It is described in Beilstein 1, 817 that glycol aldehyde is. prepared by subjecting allyl alcohol to ozone oxida- R and M have the same .tion. We have found that the compound (II) can be obtained in very high'yield by subjecting the compound (I) to ozone oxidation in the presence of formaldehyde in case where R in the compound (I) is one of the above mentioned substituents other than hydrogen atom or in -the absence of formaldehyde in case where R in the compound (I) is hydrogen atom.

The first step in the process according to the present invention is preferably carried out by ozonizing the compound (I) 'in' a suitable 'in'ert solvent such as methylene" chloride, ethyl acetate, petroleum ether, chloroform, carbon tetrachlorideand the like at a lower temperature, for example, aboutO" C. to about" 70C. and reducing the ozonized product by means of an 'o'zonidedecomposing agent, for example, acetic acid and zinc or catalytic reduction to give the compound (II).

After completionof the reaction, the reaction product, the compound (11), may be isolated from the reaction mixture by one of the conventional methods; For example, after completion of the reaction the'solid substance is filtered and washed with an organic solvent; The combined organic solvent solutions are. washed successively with sodium bicarbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent is distilled off from the dried solution and the residue is distilled under reduced pressure to give the desired compound (II).

The second step in the process according to the present invention, which involves conversion-of the compound .(Il) to the corn-pound IV), is preferably performed by reacting the compound (II) with the compounds (H1) in a suitable inert solvent. solvents include liquid ammonia, lower alkyl ethers containing from 1 to carbon atoms on the alkyl moiety, for example, diethylether, alicyclic ethers, for example, tetrahydrofuran, aromatic hydrocarbons, for example,

Examples of the organic benzene and the like. Liquid ammonia, diethyl ether and tetrahydrofuran' are the suitable inert solvents. The reaction temperature is between about 60 C. and about 100 C., and very preferably it is about room temperature. After completion of the reaction, the reaction product may be isolated from the'reaction mixture by one of the" conventional methods. For example, the solvent is removed from the reaction mixture and the residue is subjected to distillation or recrystallization from ethanol or diethyl ether to obtain the desired compound (IV).

Partial hydrogenation','which isthe third step in the process according to the present invention, is conveniently carried out by hydrogenating the compound (IV) in the presence of a rare metal catalyst such as palladium, platinum, nickel and the like with or without a suitable inertsolvent. When an inert solvent is to be used,

examples of the suitableinert solvents are ethyl acetate,

chloroform, loweralcohols containing from 1 to 5 carbon atoms, petroleum ether, glacial acetic acid, pyridine and the like. 1

The fourth step, hydroxy-lation, may be advantageously carried out by hydroxylating the compound (V) obtained the above described third step'by means of an oxidizing agent such as permanganate, for example, potassium permanganate, hydrogen peroxide, osmium tetraoxide and the like in a suitable inert solvent such as water, aqueous alcohols, lower alcohols containing from 1 to 5 carbon atoms, aqueous acetone,.acetone and the like. The reaction is carried out at a lower temperature, for example,

-';about 0 c. to about 430 ,c. After completion of the reaction, the reaction product may be isolated from the reaction mixture by one of the conventional methods. For example, after completion of the reaction, the solid material is filtered and washed with ether, then the filtrate is also extracted with-same solvent and the combined organic solution is dried and evaporated off to obtain the residue which gives the desired compound (VI) by dis- ;tillation under reduced pressure.

\ gThe'final step, mineral acid treatment, may be carried out by treating the compound (V1) with a diluted mineral acid such as dilutedhydrochlorie acid, sulfuric acid and ,thelike. product, 'which is .DL-ri'bose, may be isolated from the After completion of the reaction, thereaction reaction mixture byione of the conventional methods. For example, the reaction mixture'istreated ,with a suitableionv exchange resin to remove mineral acidused and theefiluentisl concentratedunder reduced pressure is obtain residue containing DL-ribose in crude state.

' Pure DL-ribose is obtained by acylating the crude DL- ribose with an acylating agent, for example, propionic anhydride and distillating the resulting DL-ribose tetraacylate.

The allyl alcohol derivatives having the Formula I used as the starting material is prepared as follows: the allyl alcohol derivatives having the Formula I in which R represents hydrogen atom are prepared by reacting allyl alcohol with dihydropyran or dihydrofuran in the presence of a trace of mineral acid. The allyl alcohol derivatives having (I) in which R represents one of the above mentioned substituents other than hydrogen atom are prepared by reacting butynediol With dihydropyran and/ or dihydrofuran in the presence of a trace of mineral acid and partially hydrogenating the resulting compound.

The following examples are given for the purpose of illustration and not by way of limitation.

Example 1.-Preparati0n of 2-(2'-tetrahydr0- pyranyloxy)-ethanal Formaldehyde evolved by heating of 75 g. of paraformaldehyde is introduced into 1.3 l. of methylene chloride under ice cooling. After addition of 128 g. of 1,4-di(2'-tetrahydropyranyloxy)-butene to the resulting solution, a theoretical amount of ozone is passed through the solution at 50 C. (ozone concentrationzi 6.098 g./hr.). After completion of the ozonization, the reaction mixture is transferred in a three-necked round 'bottomed flask, to which 130 g. of zinc is added. A mixture of 75 ml. of acetic acid and 3.8 ml. of Water is added to the resulting mixture under ice cooling at such a rate as to maintain the temperature of the content at about 16 to 19 C. After completion of the addition, the content of the flask i stirred at room temperature for an additional 30 minutes. At the end of the stirring the resulting mixture gives negative ozonide reaction on starch iodide paper. The solid substance is filtered and washed thoroughly with methylene chloride. Combined organic solutions are washed successively Withsodium bicarbonate solution and water, and then dried over anhydrous sodium sulfate. The methylene chloride is distilled off from the dried solution and the residue is distilled to give 9.5 g. (63.5% of thetheoretical amount) of 2-(2'-tetrahydropyranyloxy)-ethanal' boiling at 77-79 C. at 1 0 mm. Hg.

Analysis.-Calcd for C H O C, 58.25; H, 8.49. Found: C, 58.31; H, 8.39. r

Example 2.Preparati0n of 2- (2 '-tetrahydr0pyrany loxy ethanal from 3- (2-tetrahydropyranyl0xy propane-1 A theoretical amount of ozone is passed through a solution of 14.2 g. of 3-(2'-tetrahydropyranyloxy)-propene-l in ml. of methylene chloride at 50 C. After completion of the ozonization, the reaction mixture is transferred in a three-necked, round-bottomed flask and 26 g. of zinc is added to the solution to which a mixture of 15 ml. of acetic acid and 0.7 ml. of water is added under ice cooling at such a rate as to maintain the solution at 15 to 19 C. After completion of the addition, the solution is stirred at room temperature for an additional 30 minutes. At the'end of the stirring, the solution gives negative on starch iodide paper. The solution is treated by the same method as described in Example 1 to give 10.5 g. (73% 0f the theoretical amount) of 2-(2-tetrahydropyranyloxy)ethanal boiling at 77 to 79 C. at 10 mm. Hg.

Analysis.Calcd for C H O C, 58.39; H, 8.21. Found: C, 58.31; H, 8.39.

Example 3 A solution of 11.8 g. of ethyl bromide in 30 ml. of tetrahydrofuran is added slowly dropwise to amixture of 2.62 g. of metallic magnesium in 50 ml. of tetrahydro- 5 solution of 12.8 g. of propargyldiethylacetal in 30 ml. of tetrahydrofuran over about 15 minutes during which period ethane gas is evolved vigorously. After completion of the addition, the reaction mixture is stirred at room temperature for an additional hour. A solution of 12 g. of 2-(2'-tetrahydropyranyloxy)-ethanol 30 ml. of tetrahydrofuran is added dropwise to the resulting mixture while maintaining the temperature of the mixture below 35 C. The mixture is stirred for an additional 2 hours and then allowed to stand for 24 hours. The resulting reaction mixture is poured into saturated aqueous ammonium chloride solution and the organic layer is separated and dried over anhydrous sodium sulfate. The

solvent is distilled off from the dried solution and the residue is distilled under reduced pressure to obtain a fraction boiling at 141 to 142 C. at 0.1 mm. Hg. There is obtained 14 g. of 1,l-diethoxy-S-(2-tetrahydropyranyl) oxy-pent-2-yn-4-ol.

Analysis.Calcd for C H O C, 61.74; H, 8.88. Found: C, 61.52; H, 8.88.

Example 4.Preparatin of 2-ethoxy-5-(2'-tetrahydr0- pyranyl) oxymethyl-2.5-dihydr0furan 49.5 g. of Lindlars catalyst (palladium on calcium carbonate) is added to a solution of 148 g. of 1.1-diethoxy--(2'-tetrahydropyranyl) oxy-pent-2-yn-4-ol in 950 ml. of ethyl acetate and the mixture is shaken under hydrogen atmosphere until 93% of a theoretical amount of hydrogen is absorbed. After completion of the reaction, the reaction mixture is filtered to remove catalyst, which is washed with a small amount of diethyl ether. The combined filtrate and washings are distilled to remove the solvent and the residue is distilled under reduced pressure to give 78 g. of 2-ethoxy-5-(2'-tetrahydropyranyl) oxymethyl-Z.5-dihydrofuran boiling at 80 to 90 C. at 0.15 mm. Hg.

Analysis.Calcd for C H O C, 63.20; H, 8.73. Found: C, 63.21; H, 8.62.

Example 5.Preparation of 2-eth0xy-3,4-dihydr0xy-5- (2'-tetrahydropymnyl) oxymethyl-tetrahydrofuran 12.5 g. of 2-ethoxy-5-(2'-tetrahydropyranyl) oxymethyl-2,5-dihydrofuran obtained by the method described in Example 4 is added to a mixture of 65 ml. of acetone and 42 ml. of water and 7.0 g. of crystal of potassium permanganate is added portionwise to the solution at 15 to 20 C. in 2 hours under stirring. After completion of the addition, the mixture is stirred for an additional 30 minutes. After completion of the reaction, the reaction mixture is centrifuged to remove colloidal manganese dioxide, which is washed with a small amount of diethyl ether. On the other hand, the mother liquor is concentrated under reduced pressure and the residual aqueous solution is extracted with diethyl ether. The extract is combined with the above washings and the combined solutions are dried. Removal of the solvent from the solution and distillation of the residue under reduced pressure give 7.6 g. of a viscous oil boiling 150 to 160 C. (bath temperature) at 5 10- mm. Hg.

Analysis.Calcd for C H O C, 54.95; H, 8.45. Found: C, 54.96; H, 8.01.

Example 6.Preparation 0f DL-ribose A suspension of 7.5 g. of 2-ethoXy-3,4-dihydroxy-5- (2-tetrahydropyranyl) oxymethyl tetrahydrofuran in 50 ml. of 5% hydrochloric acid is allowed to stand for 3 days at room temperature. The reaction mixture is subjected to deacid-treatment with Amberlite -IR4B for de-acidification and the eflluent is concentrated under reduced pressure at room temperature. The residue is dissolved in anhydrous ethanol and to the resulting solution is added benzene sufficient to separate oily substances, which are recovered by decantation and dried under reduced pressure at room temperature to yield 3.5 g. of syrup. The syrup is subjected to ion exchangechromatrography with Dowex-l in the form of borate and elution is carried out by using 0.025 M potassium 'borate (K2B4O7) solution to yield 2.8 g. of pure DL- ribose as a syrupy substance, which has the following physical properties:

Rf value: 0.32 (Control: D-ribose; Rf value 0.32; solvent, n-butanolzwaterzacetic acid (4:5:1); temperature 20:1 0.; time 15.5 hours).

DL-ribose tetrapropionate: B.P. -165 C. (bath temperature) at 3X10- mm. Hg.

Analysis.Ca1cd for C H O C, 54.60; H, 6.95. Found: C, 54.71; H, 7.03.

1-0- acetyl 2,3,5-tri O-benzoyLfi-DL-ribofuranose: M.P.115-117 C.

Analysis.Calcd for CHI-124092 c, 66.66; H, 4.80. Found: C, 66.15; H, 4.70.

DL-ribose phenylosazone: M.P. 166-168 C.

Analysis.-Calcd fol C17HZQO3N4Z C, H, N, 17.06. Found: C, 61.31; N, 16.91. I

While specific embodiments of the invention have been shown and described in detail to illustrate the application of the inventive principles, it will be understood that this invention may be embodied otherwise without departing from such principles.

What is claimed is: 1. Process for preparing DL-ribose which comprises subjecting a compound having the formula wherein R is a member selected from the group consisting of Z-tetrahydropyranyl and Z-tetrahydrofutyl groups and R is a member selected from the group consisting of hydrogen atom, a lower alkyl group containing from 1 to 3 carbon atoms and O O-CHz- 0 OOH,-

to ozone oxidation to form a compound having the formula R--OCH -CHO wherein R has the same meaning as above, reacting the latter compound with a compound having the formula lower alkyl group containing from 1 to 3 carbon atoms to form a compound having the formula OH OR:

wherein R and R have the same meaning as above, subjecting the latter compound to partial hydrogenation in the presence of a rare metal catalyst to form a compound having the formula ROCH2 o -O 2 wherein R and R have the same meaning as above, re-

acting the latter compound with an oxidizing agent selected from the group consisting of .alkali metal permanganate, hydrogen peroxide and osmium tetraoxide to form a compound having the formula OH OH wherein R and R have the same meaning as above and treating the latter compound with a dilute mineral acid. 2. A process for preparing a compound having the.

formula ROCH2[ O/-R2 wherein R has the same meaning as above and R is a member selected from the group consisting of hydrogen atoms, a lower alkyl group containing from 1 to 3 carbon atoms,

to ozone oxidation to form a compound having the formula ROCH CHO wherein R has the same meaning as above, reacting the latter compound with a compound having the formula XMg-CECH 0R2 wherein X is a member selected from the group consisting of chlorine, bromine and iodine atoms and R has the same meaning as above 'to form a compound having the formula OR: RoGrn-oIL-OzQ-CE OH 0R2 wherein R and R have the same meaning as above, subjecting the latter compound to partial hydrogenation in the presence of a rare metal catalyst to form a compound having the formula 8 wherein R and R have the same meaning as above, reacting the latter compound with an oxidizing agent selected from the group consisting of alkali metal permanganate, hydrogen peroxide and osmium tetraoxide. 3. A process for preparing a compound having the formula wherein R is a member selected from the group consisting of Z-tetrahydropyranyl and Z-tetrahydrofuryl groups and R is a lower alkyl group containing from 1 to 3 carbon atoms which comprises subjecting a compound having the formula wherein R has the same meaning as above and R is a member selected from the group consisting of hydrogen atom, a lower alkyl group containing from 1 to 3 carbon atoms O-OHr- K oornto ozone oxidation to form a compound having the formula ROCH CH0 wherein R has the same meaning as above, reacting the latter compound with a compound having the formula wherein X is a member selected from the group consisting of chlorine, bromine and iodine atoms and R has the same meaning as above to form a compound having the formula /O a ROCHz-CHCECCH OH OR:

wherein R and R have the same meaning as above, subjecting the latter compound to partial hydrogenation in the presence of a rare metal catalyst.

4. 2 ethoxy-3 ,4 dihydroxy-S-(2'-tetrahydropyranyl) oxymethyl-tetrahydrofuran.

5. 2 ethoxy-S-(2'-tetrahydropyranyl)oxymethyl-2,5- dihydrofuran.

6. 1,1-diethoxy 5 (2'-tetrahydropyranyl)oxy-pent- 2-yn-4-ol.

No references cited.

LEWIS GOTTS, Primary Examiner.

J. R. BROWN, Assistant Examiner. 

1. PROCESS FOR PREPARING DL-RIBOSE WHICH COMPRISES SUBJECTING A COMPOUND HAVING THE FORMULA 